天然药物化学第三讲.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Overall Biosynthetic Scheme,Variables in,Polyketides,O,H,O,R,Starter,O,Side chains,Extender,Chain,length,(Combinatorial Biosynthesis),O,H,Reduction level,KR/DH/ER,OH,OH,Chirality,Polyketide Synthases(PKS),Type I PKS(Bacterial Non-iterative Modular PKS for reduced PK),II.Type II PKS,(Bacterial Iterative Non-modular PKS for aromatic PK),III.Fungal Iterative Modular PKS,AT ACP KS AT KR ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT,ACP KS,AT,KR ACP KS,AT,KR ACP KS,AT,ACP KS,AT,DH ER KR ACP KS,AT,KR ACP KS,AT,KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT,ACP,KS AT KR,ACP,KS AT KR,ACP,KS AT,ACP,KS AT DH ER KR,ACP,KS AT KR,ACP,KS AT KR,ACP,TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP,KS,AT KR,ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP,KS,AT KR ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,CO,2,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT,KR,ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP,KS,AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP,KS,AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,CO,2,AT ACP KS AT KR ACP KS AT,KR,ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT KR ACP,KS,AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP,KS,AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,CO,2,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP,KS,AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP,KS,AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,CO,2,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER,KR,ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT,DH,ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH,ER,KR ACP KS AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP,KS,AT KR ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,O,O,H,O,H,S,O,O,S,C,O,O,-,O,module 1,module 2,module 6,module 5,module 4,module 3,Load,CO,2,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT,KR,ACP KS AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP,KS,AT KR ACP TE,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP,KS AT KR,ACP TE,module 2,O,O,H,O,H,O,H,O,S,O,module 1,module 2,module 6,module 5,module 4,module 3,Load,CO,2,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP,KS AT,KR,ACP TE,module 2,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT,KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP,KS AT KR,ACP,TE,module 2,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 2,module 1,module 2,module 6,module 5,module 4,module 3,Load,AT ACP KS AT KR ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,module 2,module 1,module 2,module 6,module 5,module 4,module 3,Load,Desosamine,Cladinose,HO,OH,O,OH,O-desosamine,O-mycarose,O,O,HO,6,ATACP KS AT KR ACP KS AT KR ACP KS AT ACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,1,2,3,4,5,X,Donadio et al.(1993)PNAS,90:7119,Load,O,OH,O,O,O-,desosamine,3,5,AT ACP KS AT KR ACP KS AT KR ACP KS ATACP KS AT DH ER KR ACP KS AT KR ACP KS AT KR ACP TE,2,4,1,6,Load,O-,cladinose,OH,HO,Inactivation of a Reduction Domain in DEBS,Polyketide Synthases(PKS),II.Type II PKS,(Bacterial Iterative Non-modular PKS for aromatic PK),act,mutant of,Streptomyces coelicolor,(Brian Rudd,1976),act,mutants of,Streptomyces coelicolor,The first,act,clone,(Francisco Malpartida,1984),Streptomyces parvulus,(without and with the,act,gene cluster),The,act,Genes of,Streptomyces coelicolor,Actinorhodin,Tailoring steps,Regulation,resistance,Chain assembly,(PKS,),Polyketide Synthases(PKS),II.Type II PKS,(Bacterial Iterative Non-modular PKS for aromatic PK),Polyketide Synthases(PKS),II.Type II PKS,(Bacterial Iterative Non-modular PKS for aromatic PK),Polyketide Synthases(PKS),II.Type II PKS Expression,Polyketide Synthases(PKS),II.Type II PKS Expression,Polyketide Synthases(PKS),II.Type II PKS Expression,Polyketide Synthases(PKS),II.Type II PKS Expression,Polyketide Synthases(PKS),II.Type II PKS Expression,Polyketide Synthases(PKS),II.Type II PKS Expression,Actinorhodin,(,S.coelicolor,),Medermycin,(,S.AM-7161,),Mederhodin,First,hybrid,antibiotic,(1985),Non-Reducing-PKS,Norsolorinic acid,Tetrahydroxynaphthalene,(THN),Polyketide Synthases(PKS),III.Fungal Iterative Modular PKS,NR-PKS and PR-PKS For Aromatic PK,Polyketide Synthases(PKS),III.Fungal Iterative Modular PKS,NR-PKS and PR-PKS For Aromatic PK,Partially-Reducing-PKS,6-Methylsalicylic acid,(MSA),Polyketide Synthases(PKS),III.Fungal Iterative Modular PKS,NR-PKS and PR-PKS For Aromatic PK,6-Methylsalicylic acid,(MSA),Polyketide Synthases(PKS),IV.Fungal Iterative Modular PKS,HR-PKS For Reduced PK,Highly-Reducing-PKS,Polyketide Synthases(PKS),IV.Fungal Iterative Modular PKS,HR-PKS For Reduced PK,Lovastatin nonaketide synthase(LNKS),Polyketide Synthases(PKS),IV.Fungal Iterative Modular PKS,HR-PKS For Reduced PK,Lovastatin nonaketide synthase(LNKS),Polyketide Synthases(PKS),IV.Fungal Iterative Modular PKS,HR-PKS For Reduced PK,LNKS and P450,Lovastatin diketide synthase(LDKS),Polyketide Synthases(PKS),IV.Fungal Iterative Modular PKS,HR-PKS For Reduced PK,LNKS and P450 and LDKS and LovD,V.Plant PKS-Type III PKS,Chalcone/stilbene synthase superfamily for,plant and bacterial,PKCHS/STS Superfamily,V.Plant PKS-Type III PKS,Chalcone/stilbene synthase superfamily for plant and bacterial PKCHS/STS Superfamily,Structure of CHS,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,V.Plant PKS-Type III PKS,CHS/STS Mechanism:catalytic triad,Flavanones,naringenin,6-deoxynaringenin,V.Plant PKS-Type III PKS,how stilbenes are made?,V.Plant PKS-Type III PKS,how stilbenes are made?,V.Plant PKS-Type III PKS,The difference between CHS and STS,Cyclization:,Claisen cond.,Cyclization:,Aldol cond.,and de-CO,2,V.Plant PKS-Type III PKS,The difference between CHS and STS,Cyclization:,Claisen cond.,Cyclization:,Aldol cond.,and de-CO,2,Nonribosomal Peptide Synthetase(NRPS),PKS&NRPS Domains,Nonribosomal Peptide Synthetase(NRPS),Amino acid adenylation in peptide synthesis,Nonribosomal Peptide Synthetase(NRPS),Nonribosomal Peptide Synthetase(NRPS),Nonribosomal Peptide Synthetase(NRPS),Nonribosomal Peptide Synthetase(NRPS),Possible Condensation Mechanism,Nonribosomal Peptide Synthetase(NRPS),An example:bacitrancin,Hybrid example:epothilone,Hybrid example:epothilone,Termination:ACV synthetase for penicillin,Termination:ACV synthetase for penicillin,Isopenicillin,N,synthase(IPNS):,Non-heme iron-dependent oxidase,Comparison of NRPS and PKS,Nonribosomal Peptide Synthetase(NRPS),Terpenoids and Steroids,Terpenoids,(Based on the number of isoprene units),Hemiterpenes:1 x C5,Monoterpenes:2 x C5,Sesquiterpenes:3 x C5,Diterpenes:4 x C5,Sesterterpenes:5 x C5,Triterpenes:6 x C5,Tetraterpenes:8 x C5,Higher terpenes,Steroids:,Modified triterpenoids,Cholesterol,Vitamin D,A,Estrogens,Androgens,Artemisinin,Trichothecenes,Taxol,Ginseng,Ginkgo biloba,Geraniol C10,Menthol,Thymol,Camphor,Limonene,Citronellol,Pinene,Carvone,Farnesol C15,Geranylgeraniol C20,Squalene C30,Phytoene C40,Lycopene C40,Carotenes C40,香叶醇,金合欢醇,香叶基香叶醇,角鲨烯,八氢番茄红素,薄荷醇,没药烯,紫杉烯,Terpenoids and Steroids,The mevalonate pathway,-three acetyl CoA,2.The 1-Deoxy-D-xylulose 5-Phosphate Pathway,-Pyruvate and Glyceraldehyde 3-phosphate,The mevalonate pathway,Note:not acetoacetyl-CoA as Nu!,The mevalonate pathway,b,-,Hydroxy-,b,-methylglutaryl-CoA,(HMG-CoA),The mevalonate pathway,The mevalonate pathway,The mevalonate pathway,The mevalonate pathway,The mevalonate pathway,DMAPP is the more stable isomer,The mevalonate pathway,DMAPP:A reactive electrophile,IPP:terminal double bond-A nucleophile,Differing reactivity of the two C5 building blocks:,DMAPP+IPP:New C-C bond formation,-the basis of terpenoid biosynthesis,The 1-Deoxy-D-xylulose 5-Phosphate Pathway,Starting materials,Pyruvate(Glycolytic pathway),Glyceraldehyde 3-phosphate(Glycolytic pathway),The 1-Deoxy-D-xylulose 5-Phosphate Pathway,1.Pyruvate to 1-deoxy-D-xylulose 5-P,a-,Ketoacid decarboxylation,The 1-Deoxy-D-xylulose 5-Phosphate Pathway,1.Pyruvate to 1-deoxy-D-xylulose 5-P,TPP-catalyzed,a-,Ketoacid decarboxylation,The 1-Deoxy-D-xylulose 5-Phosphate Pathway,2.1-deoxy-D-xylulose 5-P to 2-,C,-methyl-D-erythriotol 4-P,Pinacol-like,rearrangement,NADPH,The 1-Deoxy-D-xylulose 5-Phosphate Pathway,3.2-,C,-methyl-D-erythriotol 4-P to IPP/DMAPP,CTP,ATP,The 1-Deoxy-D-xylulose 5-Phosphate Pathway,3.2-,C,-methyl-D-erythriotol 4-P to IPP/DMAPP,Monoterpenes,-Essential oils,蒎烷,薄荷烷,莰烷,异莰烷,蒈烷,小茴香烷,侧柏烷,Monoterpenes,-Essential oils,Monoterpenes,-Essential oils,香叶醇焦磷酸酯,Monoterpenes,-Essential oils,橙花醇焦磷酸酯,香叶醇焦磷酸酯,芳樟醇焦磷酸酯,Monoterpenes,-Essential oils,Monoterpenes,-Essential oils,Generation of carbocations:,Monoterpenes,-Essential oils,Fate of carbocations:,Monoterpenes,-Essential oils,Wagner-Meerwein Rearrangements:,shift of hydride,methyl,or alkyl,1,2-,1,3-,or longer shifts,Monoterpenes,-Essential oils,Wagner-Meerwein Rearrangements:,shift of hydride,methyl,or alkyl,1,2-,1,3-,or longer shifts,Monoterpenes,-Essential oils,Wagner-Meerwein Rearrangements:,shift of hydride,methyl,or alkyl,1,2-,1,3-,or longer shifts,Monoterpenes,-Essential oils,橙花醇焦磷酸酯,香叶醇焦磷酸酯,芳樟醇焦磷酸酯,Monoterpenes,-Essential oils,E,-citral(,E,-,柠檬醛,),香叶醇焦磷酸酯,牻牛儿醛,香茅醛,香茅醇,牻牛儿醇,/,香叶醇,Monoterpenes,-Essential oils,Z,-citral,橙花醛,(Z-,柠檬醛,),橙花醇焦磷酸酯,橙花醇,Monoterpenes,-Essential oils,Monoterpenes,-Essential oils,Deprotonation,Water as Nu,柠檬烯,松油醇,桉树脑,Monoterpenes,-Essential oils,a,-,水芹烯,b,-,水芹烯,a,-,蒎烯,b,-,蒎烯,小茴香酮,小茴香醇,冰片,樟脑,/,莰酮,莰烯,1,3-shift,蒈烯,a,-,松油烯,g,-,松油烯,松油烯,-4,醇,桧烯,香芹醇,香芹酮,异胡椒烯醇,异胡椒烯酮,胡椒烯酮,胡椒酮,新薄荷醇,异蒲勒酮,蒲勒酮,薄荷呋喃,薄荷醇,新薄荷醇,异薄荷醇,新异薄荷醇,异薄荷酮,薄荷酮,Sesquiterpenes,-C,15,Linear C,15,Sesquiterpenes,-C,15,Linear C,15,Sesquiterpenes,-C,15,Cyclic,C,15,Sesquiterpenes,-C,15,Cyclic C,15,-Artemisinin,Sesquiterpenes,-C,15,Cyclic C,15,-Trichothecenes,more than 150 known,Originally from Trichothecium,but most from Fusarium,Diterpenes,-C,20,Diterpenes,-C,20,Diterpenes,-C,20,Triterpenes and Steroids,-C,30,Key intermediate:Squalene,Triterpenes and Steroids,-C,30,C1 to C1 coupling,possible now!,Triterpenes and Steroids,-C,30,Steroids:cyclization of squalene via squalene-2,3-oxide,catalyzed by a flavin enzyme requiring O,2,and NADPH.,Triterpenes and Steroids,-C,30,Triterpenes and Steroids,-C,30,Triterpenes and Steroids,-C,30,Steroids,Steroids:,Modified triterpenoids,no 3 methyls at C-4 and C-14,From Lanosterol to Cholesterol,C-14 methyl removed as formic acid,From Lanosterol to Cholesterol,C-4 dimethyl removed as CO,2,From Lanosterol to Cholesterol,C-24 double bond reduced by NADPH-reductase,C-8 double bond migrated to C5 via C7,Triterpenoids-C30 Steroids-C27,Steroids from plants,fungi,and algae-C28/C29,1 or 2 extra C on C24,Tetraterpenes,-C,40,Carotenoids,Like squalene for triterpenes,Phytoene for tetraterpenes,Phytoene formation and conversion to Lycopene,Phytoene formation and conversion to Lycopene,Bacteria,Fungi/plants,Phytoene formation and conversion to Lycopene,From Lycopene to Carotenes,From Lycopene to Other Carotenoids,From Lycopene to Carotenoids:ring formation,From,b,-Carotene to Vitamin A,Higher Terpenes,Cis,double bond,Loss of,Pro-S,H of IPP,The Shikimate Pathway,Aromatic Amino Acids and Phenylpropanoids,Aromatic amino acids,Benzoic acids,Cinnamic acids,Modified:,Lignans and lignin,Phenylpropenes,Coumarins,.,Combined with PK/FA:,Styrylpyrone,Flavonoids and stilbenes,Flavonolignans,Isoflavonoids,.,Plants and Microbes,Not in animals,Essential amino acids from diets,Shikimic acid:,the central intermediate in the pathway,Originally isolated from,Illicium,species,(Shikimi in Japanese),The Shikimate Pathway,Aromatic Amino Acids and Phenylpropanoids,Phenylpropanoids:,C,6,C,3,Unit,Cinnamic acids,Coumarins,Lignans(polymers of hydroxycinnamyl alcohols),Flavonoids.,The Shikimate Pathway,Aromatic Amino Acids and Phenylpropanoids,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From chorismic acid to benzoic acid,In bacteria;,plants use cinnamic acid to produce benzoic acid,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From chorimic acid to aromatic acids,Recall:,6-MSA by PKS,In bacteria;,plants use cinnamic acid to produce salicylic acid,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From chorismic acid to aromatic acids,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From chorismic acid to aromatic acids,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From anthranilic acid to tryptophan,The Shikimate Pathway,Aromatic amino acids and simple benzoic acids,-,From anthranilic acid to tryptophan,Aromatic amino acids and simple benzoic acids,-,From chorismic acid to prephenic acid,Prephenic acid,Enolpyruvate:C-O bond to the ring,Pyruvate:C-C bond to the ring,Aromatic amino acids and simple benzoic acids,-,From to prephenic acid to phenylalanine,Aromatic amino acids and simple benzoic acids,-,From to prephenic acid to tyrosine,Prephenic acid,Aromatic amino acids and simple benzoic acids,-,From to prephenic acid to other